IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58879-z.html
   My bibliography  Save this article

Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Author

Listed:
  • Robert I. McGeachan

    (The University of Edinburgh
    The University of Edinburgh
    The University of Edinburgh)

  • Soraya Meftah

    (The University of Edinburgh
    The University of Edinburgh)

  • Lewis W. Taylor

    (The University of Edinburgh
    The University of Edinburgh)

  • James H. Catterson

    (The University of Edinburgh
    The University of Edinburgh)

  • Danilo Negro

    (The University of Edinburgh
    The University of Edinburgh)

  • Calum Bonthron

    (The University of Edinburgh
    The University of Edinburgh)

  • Kristján Holt

    (The University of Edinburgh
    The University of Edinburgh)

  • Jane Tulloch

    (The University of Edinburgh
    The University of Edinburgh)

  • Jamie L. Rose

    (The University of Edinburgh
    The University of Edinburgh)

  • Francesco Gobbo

    (The University of Edinburgh
    The University of Edinburgh)

  • Ya Yin Chang

    (The University of Edinburgh)

  • Jamie Elliott

    (The University of Edinburgh
    The University of Edinburgh)

  • Lauren McLay

    (The University of Edinburgh
    The University of Edinburgh)

  • Declan King

    (The University of Edinburgh
    The University of Edinburgh)

  • Imran Liaquat

    (Royal Infirmary of Edinburgh)

  • Tara L. Spires-Jones

    (The University of Edinburgh
    The University of Edinburgh)

  • Sam A. Booker

    (The University of Edinburgh
    The University of Edinburgh)

  • Paul M. Brennan

    (Royal Infirmary of Edinburgh
    The University of Edinburgh
    The University of Edinburgh)

  • Claire S. Durrant

    (The University of Edinburgh
    The University of Edinburgh)

Abstract

In Alzheimer’s disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ and other biomarkers relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses in living adult human brain. Using live human brain slice cultures, we report that Aβ1-40 and tau release levels vary with donor age and brain region, respectively. Release of other biomarkers such as KLK-6, NCAM-1, and Neurogranin vary between brain region, while TDP-43 and NCAM-1 release is impacted by sex. Pharmacological manipulation of Aβ in either direction results in a loss of synaptophysin puncta, with increased physiological Aβ triggering potentially compensatory synaptic transcript changes. In contrast, treatment with Aβ-containing Alzheimer’s disease brain extract results in post-synaptic Aβ uptake and pre-synaptic puncta loss without affecting synaptic transcripts. These data reveal distinct effects of physiological and pathological Aβ on synapses in human brain tissue.

Suggested Citation

  • Robert I. McGeachan & Soraya Meftah & Lewis W. Taylor & James H. Catterson & Danilo Negro & Calum Bonthron & Kristján Holt & Jane Tulloch & Jamie L. Rose & Francesco Gobbo & Ya Yin Chang & Jamie Ellio, 2025. "Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58879-z
    DOI: 10.1038/s41467-025-58879-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58879-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58879-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Dominic M. Walsh & Igor Klyubin & Julia V. Fadeeva & William K. Cullen & Roger Anwyl & Michael S. Wolfe & Michael J. Rowan & Dennis J. Selkoe, 2002. "Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo," Nature, Nature, vol. 416(6880), pages 535-539, April.
    2. Jeff Sevigny & Ping Chiao & Thierry Bussière & Paul H. Weinreb & Leslie Williams & Marcel Maier & Robert Dunstan & Stephen Salloway & Tianle Chen & Yan Ling & John O’Gorman & Fang Qian & Mahin Arastu , 2016. "The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease," Nature, Nature, vol. 537(7618), pages 50-56, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Xiuhua Yin & Hong Zhou & Mengling Zhang & Juan Su & Xiao Wang & Sijie Li & Zaixing Yang & Zhenhui Kang & Ruhong Zhou, 2023. "C3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Ya Zhu & Xiaowen Lin & Xin Zong & Shuo Han & Mu Wang & Yuxuan Su & Limin Ma & Xiaojing Chu & Cuiying Yi & Qiang Zhao & Beili Wu, 2022. "Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Shangran Qiu & Matthew I. Miller & Prajakta S. Joshi & Joyce C. Lee & Chonghua Xue & Yunruo Ni & Yuwei Wang & Ileana Anda-Duran & Phillip H. Hwang & Justin A. Cramer & Brigid C. Dwyer & Honglin Hao & , 2022. "Multimodal deep learning for Alzheimer’s disease dementia assessment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Begoña López-Arias & Enrique Turiégano & Ignacio Monedero & Inmaculada Canal & Laura Torroja, 2017. "Presynaptic Aβ40 prevents synapse addition in the adult Drosophila neuromuscular junction," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-22, May.
    5. Jusung An & Kyeonghwan Kim & Ho Jae Lim & Hye Yun Kim & Jinwoo Shin & InWook Park & Illhwan Cho & Hyeong Yun Kim & Sunghoon Kim & Catriona McLean & Kyu Yeong Choi & YoungSoo Kim & Kun Ho Lee & Jong Se, 2024. "Early onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Yuwen Chen & Haoyu Yang & Yan Luo & Yijun Niu & Muzhou Yu & Shanjun Deng & Xuanhao Wang & Handi Deng & Haichao Chen & Lixia Gao & Xinjian Li & Pingyong Xu & Fudong Xue & Jing Miao & Song-Hai Shi & Yi , 2024. "Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN) for cross-modal individual analysis of the whole brain," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Byung Jo Choi & Min Hee Park & Kang Ho Park & Wan Hui Han & Hee Ji Yoon & Hye Yoon Jung & Ju Yeon Hong & Md Riad Chowdhury & Kyung Yeol Kim & Jihoon Lee & Im-Sook Song & Minyeong Pang & Min-Koo Choi &, 2023. "Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Maher A Dayeh & George Livadiotis & Saber Elaydi, 2018. "A discrete mathematical model for the aggregation of β-Amyloid," PLOS ONE, Public Library of Science, vol. 13(5), pages 1-13, May.
    9. Fabian Wirth & Fabrice D. Heitz & Christine Seeger & Ioana Combaluzier & Karin Breu & Heather C. Denroche & Julien Thevenet & Melania Osto & Paolo Arosio & Julie Kerr-Conte & C. Bruce Verchere & Franç, 2023. "A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Xiaohang Li & Jin Cui & Yang Yu & Wei Li & Yujun Hou & Xin Wang & Dapeng Qin & Cun Zhao & Xinsheng Yao & Jian Zhao & Gang Pei, 2016. "Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-19, March.
    11. Li, Huixia & Zhao, Hongyong, 2022. "Mathematical model of Alzheimer’s disease with prion proteins interactions and treatment," Applied Mathematics and Computation, Elsevier, vol. 433(C).
    12. Mookyung Cheon & Iksoo Chang & Sandipan Mohanty & Leila M Luheshi & Christopher M Dobson & Michele Vendruscolo & Giorgio Favrin, 2007. "Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils," PLOS Computational Biology, Public Library of Science, vol. 3(9), pages 1-12, September.
    13. Janine Kutzsche & Nicoleta Carmen Cosma & Gunther Kauselmann & Friederike Fenski & Christine Bieniek & Tuyen Bujnicki & Marlene Pils & Oliver Bannach & Dieter Willbold & Oliver Peters, 2025. "Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    14. Andrew C Gill, 2014. "β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-17, January.
    15. Sheng Chen & Anuradhika Puri & Braxton Bell & Joseph Fritsche & Hector H. Palacios & Maurie Balch & Macy L. Sprunger & Matthew K. Howard & Jeremy J. Ryan & Jessica N. Haines & Gary J. Patti & Albert A, 2024. "HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Nathalie Khoury & Michelle E. Pizzo & Claire B. Discenza & David Joy & David Tatarakis & Mihail Ivilinov Todorov & Moritz Negwer & Connie Ha & Gabrielly L. Melo & Lily Sarrafha & Matthew J. Simon & Da, 2025. "Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    17. Noah S Bieler & Tuomas P J Knowles & Daan Frenkel & Robert Vácha, 2012. "Connecting Macroscopic Observables and Microscopic Assembly Events in Amyloid Formation Using Coarse Grained Simulations," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-10, October.
    18. Jiyeon Lee & Haeryung Lee & Hyein Lee & Miram Shin & Min-Gi Shin & Jinsoo Seo & Eun Jeong Lee & Sun Ah Park & Soochul Park, 2023. "ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58879-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.